3-acyloxy-7,11-keto-delta8,22 ergostadienes



atent ()fifice 2,854,464 Patented Sept. 30, 1958 2,854,464 3-ACYLOXY-7,1I KJE'IO-A ERGOSTADIENES No Drawing. Original application March 10, 1951, Serial No. 215,026. Divided and this application September 20, 1951, Serial No. 247,562

2 Claims. (Cl. 260-3971) This application is a divisional of copending application Serial No. 215,026, filed March 10, 1951, and now abandoned.

This invention is concerned with novel chemical compounds of the cyclopentanopolyhydrophenanthrene series and processes for preparing the same; more particularly, it relates to novel cyclopentanopolyhydrophenanthrene compounds having functional substituents in ring C; and specifically it relates to new compounds having a hydroxyl or keto substituent at the 11 position, and to processes for the preparation of such compounds.

Compounds of the adrenal cortex, such as Kendalls compound E (Cortisone) have been found to be of great value in the treatment of various diseases. Further, it is likely that Kendalls compound E and/or other closely related ll-hydroxy steroids will find increasing therapeutic use in the future. Unfortunately, the only method for the preparation of such compounds presently available utilizes desoxycholic or cholic acids as the starting material. Cholic and desoxycholic acids have hydroxy substituents in ring C at the 12 position, thus providing a means for introducing a functional substituent at the 11 position. However cholic and desoxycholic acids, which are obtained from animal bile, are only available in limited amounts. Heretofore no practical method was available whereby a functional group could be introduced in ring C which would permit the use of more abundant steroids such as the sterols, ergosterol, cholesterol, stigmasterol, or plant sapogenins, such as diosgenin, tigogenin, and the like.

It is, an object of the present invention to provide a process for introducing a functional group in ring C at the 11 position. It is a further object to provide a process for converting cyclopentanopolyhydrophenanthrene compounds having a double bond in the 7 :8 position to the corresponding cyclopentanopolyhydrophenanthrene compound having a hydroxyl or keto group at positions 7 and 11. Another object is to provide new compounds of the steroid series having functional groups in ring C suitable for the preparation of other cyclopentanopolyhydrophenanthrene compounds. Other objects will be apparent from the detailed description hereinafter provided.

In accordance with our invention, we have now found.

that compounds of the cyclopentanopolyhydrophenanthrone series having an ll-keto substituent can be synthesized by reactions indicated as follows:

IV IIIA IIIB VII These reactions are carried out as follows:

A cyclopentanopolyhydrophenanthrene compound having a 7:8 double bond (I) is reacted 'with mercuric acetate producing the corresponding compound having conjugated double bonds in (II) which is treated with a per acid, thus forming an epoxide represented by the alternate Formulas 111A and (At present the exact structure of the epoxide IIIB. is not known and it is represented by the alternative Forms IIIA and IIIB. Alternatively it is possible that the product obtained is a mixture of these two forms.) This epoxide is then treated with an adsorbent to form the corresponding A -7,11-dihydroxy Compound IV.

The A -7,11-dihydroxy Compound IV is reacted with 7,1l-diketo Compound VI. The saturated diketo corn pound is then reduced to eliminate the 7-k'eto substituent,

thus producing the corresponding ll-ketoCompound g p The latter' compounds 'are useful intermediates for the preparation of ll-keto compounds having desirable therapeutic properties.

The E -compounds of the cyclopentanopolyhydrophenanthrene series are conveniently prepared by reacting the corresponding N-compound with mercuric acetate.

We have found that this reaction is preferably effected by. reacting the A' -compound with mercuric acetate and glacial acetic acid in the presence of a suitable solvent medium such as chloroform. The reaction is conveniently conducted by stirring. the reaction mixture for 16-24 hours. After the reaction is completed,v the A -compound is recovered from the reaction mixture by removing the precipitated mercurous acetate, and concentrating the solution under diminished pressure. If

desired, the residue may be further purified by crystallization from suitable solvents. Thus, this process can be utilized to prepare A -pregnadiene-3-ol-20-one-3- acetate, and A -dehydrotigogenin acetate from A the 7:8 and 9:11 positions Further, the 3-hydroxy-A -choladienic acid, which is also useful as a starting material in the processes of 7 our invention, is readily obtained by reducing 3 -hydroxy; 12-keto-A -choladienic acid. This is conveniently accomplished by reacting the keto acid with hydrazine hydrate and an alkali metal hydroxide in the presence of a suitable high boiling solvent such as diethylene glycol.

This invention is concerned with compounds of the type represented by intermediates V and VI above, and with processes of producing the same. Compounds V and VI may be represented by the following formulas:

The starting materials used in the process of this invention, namely the A -dihydroxy compounds shown by Formula IV, may be obtained as described in coperiding application Serial No. 215,026, now abandoned, filed March 10, 1951.

Pursuant to our invention, we have found that the A 7,11-dihydroxy compounds are readily oxidized to obtain a new series of compoundshavinga double bond in the 8:9 position and keto substituents in the 7 and 11 positions. This oxidation is readily accomplished for example by treating the A -7,11-dihydroxy compounds with chromic acid in the presence of an acid such as acetic or sulfuric acid. We have found that an oxidation mixture consisting of chromic acid-acetone-sulfuric acid is particularly useful. for this oxidation, and results in the obtainment of maximum yields of the desired diketo compound .under optimum conditions. In carrying out this process, it is necessary to protect any other hydroxyl substituents, for example, a 3-hydroxy group, by converting this group to an acyloxy substituent. After the oxidation, any such acyloxy substituents can be readily hydrolyzed to prepare the corresponding hydroxy compounds. I

These new A -7,11-diketocyclopentanopolyhydrophen v anthrene compounds are reduced to saturate the 8:9 double bonds and produce .thecorresponding saturated 7,11diketo compound. This reduction is conveniently accomplished for example by reacting the A compound with zinc in the presence of acetic acid.

In accordance with the above-described methods, cyclopentanopolyhydrophenanthrene compounds having 7,11 diketo substituents such as, 3-acyloxy-7,1l-diketo-A ergostadiene, 3-acyloxy-7,1 1-diket0-A -bisnrall0cholenic acid and-its esters, 3-acyloxy-7,1l-diketo-n -cholenic acid and its esters, 3-acyloxy7,ll-diketo-d -tigogenin, A -allopregnene-3-ol-7,11-20-trione and its acyl derivatives, and

the like can be obtained by the oxidation of the corres-.

ponding 7,11-dihydroxy compounds. Further, these diketo compounds may be reduced to the corresponding compounds having a saturated bond in the 8:9 position.

The following examples are presented to illustrate specific embodiments of our invention.

EXAMPLE 1 Preparation of 3-acetoxy-7J1-diket0-A -ergqstadiene,-

A -ergostadiene suspended in cc. of acetic acid product separated which was extracted with benzene.

The residue obtained after the removal of the benzene in vacuo crystallized readily from methanol in the form of compact rosettes of small needles. Yield: 40 mg. M. P. 12.1-123 C.; max. 2650 A., E% 147. Further purification by chromatography over alumina yielded pure 3- acetoxy-7,11-diketo-A -ergostadiene; M. P. 135l36 C. Analysis.Calc. for C H O C, 76.88; H, 9.46. Foundz C, 76.91; H, 9.58.

r max. 2660A. (E% 200-iso-octane) max. 2700 A (E% 186ethanol) a +18i2(1% CHCl EXAMPLE 2 Preparation of 3-acetoxy-7,11-diket0-A -ergostadiene from 3-acet0xy-7,1 1-dihydroxy-A -ergostadiene To a stirred suspension of 2.36 g. of 3-acetoxy-7,lldihydroxyfA -ergostadiene in 50ml. of purified acetonewasadded a solution of 6.65 millimols of chromic oxide in 5 ml. of 3.6 N sulfuric acid. The mixture was stirred at 10. C. forv 10 minutes, after which 2 ml. water was added, and themixture was stirred for 25 minutes at room temperature. The green inorganic material which had separated was removed by filtration. was stirred while '50 ml. water were added. The product wascollected on a filter and Washed with water. After drying in vacuo over phosphorous pentoxide the product, 3-acetoxy-7,11-diketo-d i -ergostadiene, was obtained in the form of a lightyellow powder. Yield: 2.26 g., M. P. 103-1 14 C. k max. 2660 (E% 121-ethanol).

EXAMPLE 3 Preparation of 3-acetoxy-7,1 1 -diket0-A -erg0stene from 3-acet oxy-7,11-diket0-A -ergostadiene A hot solution of 100 mg. of 3-acetoxy-7,11-diketod -ergostadiene-in 5 cc. of acetic acid and 0.1 cc. of water was treated with 250 mg. of zinc. The initially yellow solution was decolorized rapidly'and the mixture heated on the steam bath forthree hours. Water was then added to precipitate the diketone, which was dissolved in benzene. Upon removal of the benzene,,a residue was obtained which was recrystallized from methanol. Yield: mg.; M. P. 196-198 C.; a 25 (1.0% CHCI Analysis.--Calc. for C H O C, 76.55; H, 9.85. Found: C, 76.68; H, 9.59.

Alkaline hydrolysis of 3-acetoxy-7,1l-diketo-A -ergostene yielded 3-hydroxy-7,1l-diketo-d -ergostene, M. P. 198199 C.

Analysis-Cale. for C H O C, 78.46; H, 10.37. Found: C, 78.28; H, 10.09.

EXAMPLE 4 Preparation of methyl 3-acetoxy-7,1l-diketo-A -bisnorallocholenate from methyl 3-acet0xy-7J1-dihydr0xy- A -bisnorallocholenate To a stirred solution of 1.60 g. of methyl 3-acetoxy- 7,11-dihydroxy-M-bisnorallocholenate in 30 ml. of glacial acetic acid, was added a solution of 0.730 g. of sodium dichromate dihydrate in 30 ml. of glacial acetic acid over a period of 15 minutes. After stirring at 25 C. for two hours, the mixture was concentrated in vacuo to a small volume. The residue was shaken with 50 ml. of benzene and 50 ml. of water. The aqueous layer was extracted twice with 25 ml. portions of benzene. The combined benzene extracts were washed with 50 ml. of water, dried over anhydrous sodium sulfate, and the benzene was removed by vacuum distillation. The residual oil was triturated with 3 ml..of cold methanol and a ,the resulting crystalline product was collected and washed was treated with mg. of sodium dichrornate. With gentle swirling, the product dissolved rapidly, the resulting green solution was diluted with water, and a gummy with cold methanol. Yield 550 mg, M. P. l83185.5 C. After two recrystallizations from methanol, the melting point of the diketo compound was raised to 186.5-

187.5 C. M1 :+38.7(C=1.04,'CHCl max. 2700; E% 212. t

Analysis-Cale for C H O C, 69.74; H, 7.96. Found: C, 70.00; H, 8.12. v

EXAMPLE 5 V Methyl 3-hydroxy-11-keto bisrtorallocholahute benzene and water, 50% sulfuric acid added until an acid CODH AcO =0 A00 I 0 r: I n

0000B. oooon.

AcO- no III IV One gram of 3-acetoxy-7,ll-diketo-A -ergostene (I) obtained as described in Example 3 was dissolved in 100 cc. of chloroform and ozone Was passed through at ice bath temperature until the approximate theoretical amount of ozone Was absorbed. The reaction mixture was diluted with 100 cc. of glacial acetic acid, cooled to 5 C. and oxidized with 0.5 g. chromic acid dissolved in 0.75 cc. water and 50 cc. glacial acetic acid.

After standing overnight, 5 cc. of methanol was added and the solvent was removed in vacuo to practically dryness. The residue in the flask was dissolved by shaking twice with a mixture of 25 cc. of 5% sulfuric acid and 50 cc. of benzene. The combined benzene solutions were dried over anhydrous magnesium sulfate, and the benzene was evaporated on the steam bath in a stream of nitrogen.

The residue was dissolved in 200 cc. of ether and stirred with 5 g. of sodium carbonate and 2 cc. of water for 21 hours. The sodium salt of 3-acetoxy-7,l1-diketobisnorallocholanic acid (II) was filtered off and dried in a vacuum desiccator.

The dried sodium salt was suspended in 25 cc. of ether and 25 cc. of 50% sulfuric acid was added in small portions until the mixture was definitely acid. 100 cc. of ether was added to bring about complete solution of all solids. The aqueous layer was separated and extracted once with 50 cc. of ether.

The combined ethereal solutions were dried over anhydrous magnesium sulfate and then evaporated on the steam bath to a small volume, whereupon 3-acetoxy-7,11- diketo-bisnorallocholanic acid (II) crystallized out. The product was recrystallized from ether; M. P. 235-238" C [a] =24.6 a=0.68 C=1.38% CHCl Analysis.Calcd for C I-1 0 C, 68.87; H, 8.19. Found: C, 68.67; H, 8.04.

125 mg. of 3-acetoxy-7,11-diketo-bisnorallocholanic acid was suspended in 25 cc. of ether and esterified with diazomethane. All solid dissolved and on evaporation of the ether to a small volume, the methyl ester (III) crystallized. M. P. 226.5229 C. Mixed melting point with an authentic sample of the ester: 227-230" C.

5 g. of methyl 3-acetoxy-7,l1-diketo-bisnorallocholanate (III) and 2.07 g. of powdered potassium hydroxide reaction was obtained. The benzene layer was separated, and the'aqueous layer extracted three times with 50 cc.

of. benzene. The combined benzene solutions were washed with water and dried over anhydrous magnesium sulfate.

The benzene was treated with.Darco. The benzene solution was concentrated in vacuo to dryness, the residue was dissolved in ether and esterified with an ethereal solution of diazomethane. Theether was evaporated,

and the methyl 3-hydroxy-11-keto bisnorallocholanate (IV) wa recrystallized from methanol, M. P. 177.5-

180.5. Mixed M. P. with an authentic sample, 177-179 C. [a] =+4l.,

EXAMPLE 6 Preparation of methyl 3-acet0xy-7,1I-diketo-bisnorallocholanate grom methyl 3-acetoxy-7,11-diketo-A -bis- K norallocholenate A mixture of 400 g. of methyl 3-acetoxy-7,11-diketo A -bisnorallocholenate, 20 ml. of glacial acetic acid, 0.4 ml. water, and 1.5 g. zinc dust was heated for one hour on the steam bath. One gram of zinc dust was added, and the mixture was heated for two hours more. After cooling to room temperature, 50 ml. water were added to the mixture. The precipitated product, along with residual zinc, was collected on a filter. The dried mixture was extracted with benzene. After removal of the benzene by vacuum distillation, the product, methyl 3-acetoxy-7,11-diketo-bisnorallocholanate was recrystallized from methanol. Yield: 270 mg. M. P. 230-2315 C. The analytical sample was recrystallized from methanol, M. P. 230.5231.5 C. [a] -14.5 (C=1.55, CHClg).

Analysis.-Calc. for C H O C, 69.41; H, 8.39. Found: C, 69.70; H, 8.40.

EXAMPLE 7 Preparation of methyl 3-acetoxy-7,1l-diketo-A -cholenate from methyl 3-acet0xy-7,1l-dihydroxy-A -cholenate To a stirred suspension of 1.7 g. of methyl 3-acetoxy- 7,11-dihydroxyA -cholenate in 100 cc. acetone was added at 20 C. with stirring a solution of 0.5 g. chromium trioxide in 4 cc. of 10% sulfuric acid over a period of ten minutes. After addition was complete, the mixture was stirred for one and one half hours. The inorganic residue was filtered oh and washed with three 10 cc. portions of acetone. The acetone solution was added with stirring to 66 cc. Water and the 7,11-diketo compound which precipitated was filtered, washed free of acid with water and dried. Yield: 1.57 g.; M. P. l2.5113.5 C.

After recrystallization from ethanol the product, methyl 3-acetoxy-7,1l-diketo-A -cholenate melted at 114-1 15 C.

Analysfs.-Calc. for C H O C, 70.40; H, 8.75. Found: C, 70.93; H, 8.30.

EXAMPLE 8 Preparation of methyl 3-acet0xy-7, 11-diket0-cholanate from methyl 3-acetoxy-7,1l-diketo-A -cholenate A mixture of 1.57 g. of methyl 3-acetoxy-7,11-diketo- A -cholenate, 17 cc. acetic acid, 1.7 cc. water and 3.4 g. zinc dust was heated on a steam bath for one hour.

The reaction mixture was diluted with cc. benzene and the zinc residue was filtered ofi. The benzene solution was washed free of acid with water, dried over anhydrous sodium sulfate and concentrated to dryness. Yield 1.57 g.

The product was purified..by recrystallizationufrom ethanol; Yield: 1.17 g.; M. P1.162.3 C. t

Analysis.-Calc.;forC -M C, 70.10; H, 9.15.

Found: C, 70.52; H, 8.65.

EXAMPLE 9. Preparation of 3-ac'et0xy-7,11 diketa-8-dehydrotigogenin from 3-acet0xy-7,11 dihydroxy-8-dehydr0tigogenin To a'suspension.of.O. 346.g. (0.7.1. millimol) of. 3:-acetoxy-7,11-dihydroxy 8-dehydrotigogenin:in 10 ml. of acetone was added 0.8 ml. of a solution of 1.06 millimols' of chromium trioxide': in 3.6.Nsulfun'e acid; After stir-.. ring for 15minutes; the chromium salts which 'had' formed were removed by filtration and were washed'iwith 5 'ml. of acetone. The filtratewa streated with 50-60 ml. of water: to precipitate' the productwhich, after drying, weighed 0.283 g., M. P; 190-200 0. After two recrystallizations from methanol, 3-acetoxy-7,1l diketo-8-dehy-' drotigogenin was obtained as pale yellow needles; M. P;

226-227 C. [a] 14 (c=0.813, CHCl max. (in ethanol) 2700,

EXAMPLE Preparation of 3-acet0xy-7,11-diket0tigogenin from -3- acetoxy-7 ,1 1-diketo-8-dehydrotig0genin' A mixture of 130 mg. of 3-acetoxy-7,1l-diketo-S-dehydrotigogenin, 4 ml. glacial acetic acid, one drop of water,

and 400 mg. of zinc dust was heated on the steam bath for one hour. The mixture was cooled, and m1. of water 1 and 20 ml. of chloroform were added. After shaking thoroughly and filtering, the layers were separated, and. the aqueous layer was extracted twice with five ml. por

tions of chloroform. The combined chloroform extracts were dried over sodium sulfate,.and concentrated in vacuo. Recrystallization of the residue gave small rectangular prisms. .Yield mg., M. P. 24l-243 C., [u] 72 (c=0.827, CHCl EXAMPLEILI Preparation of it' allopregnene-3-0l-7,1L20-trione-3-acetate'from A -aHbP'regnne-SJJ1-triol-20-ane-3-acetate Seven hundred and eighty milligrams of A -allopregnene-3,7,11-triol-20-one-3-ctate"in 20 ml. of acetone were oxidized -with 2: 6 6 millimols of chromium'trioxide in 2 ml. of 10% aqueous sulfuric acid. After isolating the produchin the usual way, itwas recrystallized from methanol to give 260 mg. of paley'ellow prisms, M. P.

l77-l79 C., [a] +7l (C=l.l2, CHCl k max. 2690, 1

Elk 226 EXAMPLE 12 Preparation of allopregnan 3-ol-7J1,20-trion-3-acetale from A -allopregnene-3-0l-7J1,20-tri0ne-3=acetate A mixture of 21'0-mg.of' A -allopregnene-ll-ol 7,1l,

2. A 3-acyloxy-7;11-diket6 A -ergostadiene wherein the acyl substituent is a lower fatty acid radical.

References Cited ill-the file of this patent ""Wettsteimet a1.: HClV-"ChlmHACw, vol. 30, pp. 1262-51 RuZickaetaL: Helv.-Chim. Acta, 27, 472-489 (1944). Doree1et al.:.'Jour. Chem. Soc., 1948,-988990. Doree et.a1.: JouruChem; Soc.,' 1949, 570-575. Elseviers"Encyclopedia-off Organic Chemistry, vol. 14,

Supplement, pages 1266s-zl2-70s, 1300s (1952). 

2. A 3-ACYLOXY-7,11-DIKETO-$8,22-ERGOSTADIENE WHEREIN THE ACYL SUBSTITUENT IS A LOWER FATTY ACID RADICAL. 